Genetic factors affecting progression of nonalcoholic fatty liver disease

Abstract

Non-alcoholic fatty liver disease (NAFLD) ranges from steatosis to the more progressive form non-alcoholic steatohepatitis. Genetic factors may be important risk determinants for disease progression. This study aimed to assess association of polymorphisms in candidate genes with NAFLD severity and to investigate functional significance of selected polymorphisms Two approaches were used for association studies, case-control analysis on adults (n=351) with biopsy-proven NAFLD and transmission disequilibrium on family trios (n=71) with an index child with NAFLD. A total of 37 polymorphisms in 14 candidate genes selected on the basis of either biological relevance or previous data suggesting a role in NAFLD were genotyped. Significant differences were seen for polymorphisms in 4 genes between stages of NAFLD or in transmission within families. For SOD2, which encodes manganese-dependent superoxide dismutase, the homozygous T genotype for rs4880 was more common in severe fibrosis (OR 2.23 (95% CI 1.19-4.17); p=0.01) and the T-allele was preferentially transmitted in the family trios (p=0.038). For the adiponutrin gene (PNPLA3), carriage of the variant G-allele (rs738409) was associated with severe steatosis (OR 1.87 (95% CI 1.15-3.04); p=0.01) and severe fibrosis (OR 2.02 (95% CI 1.29-3.1); p=0.002) in adults and preferentially transmitted in the family trios (p=0.001). For the claudin-10 gene (CLDN10), carriage of rs4143093 was associated with severe steatosis (OR 2.82 (95% CI 1.5-5.3); p=0.0009). To further assess the relevance of claudin-10 to NAFLD, immunohistochemistry was performed. Expression in liver sections was confirmed. The effect of rs4143093 genotype on expression was investigated but insufficient samples were available to reach a firm conclusion. For the gamma-glutamyl cysteine ligase catalytic subunit gene (GCLC), rs17883901 was preferentially transmitted in the family trios (p= 0.046), but did not affect disease severity in adults. Studies on functional significance of this polymorphism showed that no significant difference in promoter activity between allelic variants.